tbuckley/cabot-search huggingface dataset:
CDC: 90% of Congenital Syphilis Cases Could Have Been Prevented
Authors: Emily Harris
Journal: JAMA (2023)

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Attention-Deficit/Hyperactivity Disorder Medications and Long-Term Risk of Cardiovascular Diseases
Authors: Le Zhang, Lin Li, Pontus Andell, Miguel Garcia-Argibay, Patrick D. Quinn, Brian M. D’Onofrio, Isabell Brikell, Ralf Kuja-Halkola, Paul Lichtenstein, Kristina Johnell, Henrik Larsson, Zheng Chang
Journal: JAMA Psychiatry (2023)

Use of attention-deficit/hyperactivity disorder (ADHD) medications has increased substantially over the past decades. However, the potential risk of cardiovascular disease (CVD) associated with long-term ADHD medication use remains unclear.
Detecting host responses to microbial stimulation using primary epithelial organoids
Authors: Jette Bornholdt, Christina V. Müller, Maria Juul Nielsen, Jesper Strickertsson, Daria Rago, Yun Chen, Grzegorz Maciag, Jonathan Skov, Anja Wellejus, Pawel J. Schweiger, Stine L. Hansen, Christa Broholm, Ismail Gögenur, Martti Maimets, Stine Sloth, Jakob Hendel, Adam Baker, Albin Sandelin, Kim B. Jensen
Journal: Gut Microbes (2023)

The intestinal epithelium is constantly exposed to microbes residing in the lumen. Traditionally, the response to microbial interactions has been studied in cell lines derived from cancerous tissues, e.g. Caco-2. It is, however, unclear how the responses in these cancer cell lines reflect the responses of a normal epithelium and whether there might be microbial strain-specific effects. To address these questions, we derived organoids from the small intestine from a cohort of healthy individuals. Culturing intestinal epithelium on a flat laminin matrix induced their differentiation, facilitating analysis of microbial responses via the apical membrane normally exposed to the luminal content. Here, it was evident that the healthy epithelium across multiple individuals (n = 9) demonstrates robust acute both common and strain-specific responses to a range of probiotic bacterial strains (BB-12Ⓡ, LGGⓇ, DSM33361, and Bif195). Importantly, parallel experiments using the Caco-2 cell line provide no acute response. Collectively, we demonstrate that primary epithelial cells maintained as organoids represent a valuable resource for assessing interactions between the epithelium and luminal microbes across individuals, and that these models are likely to contribute to a better understanding of host microbe interactions.
Development of Resistance to Type II JAK2 Inhibitors in MPN Depends on AXL Kinase and Is Targetable
Authors: Tamara Codilupi, Jakub Szybinski, Stefanie Arunasalam, Sarah Jungius, Andrew C. Dunbar, Simona Stivala, Sime Brkic, Camille Albrecht, Lenka Vokalova, Julie L. Yang, Katarzyna Buczak, Nilabh Ghosh, Jakob R. Passweg, Alicia Rovo, Anne Angelillo-Scherrer, Dmitry Pankov, Stefan Dirnhofer, Ross L. Levine, Richard Koche, Sara C. Meyer
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Myeloproliferative neoplasms (MPN) dysregulate JAK2 signaling. Because clinical JAK2 inhibitors have limited disease-modifying effects, type II JAK2 inhibitors such as CHZ868 stabilizing inactive JAK2 and reducing MPN clones, gain interest. We studied whether MPN cells escape from type ll inhibition. Experimental Design: MPN cells were continuously exposed to CHZ868. We used phosphoproteomic analyses and ATAC/RNA sequencing to characterize acquired resistance to type II JAK2 inhibition, and targeted candidate mediators in MPN cells and mice. Results: MPN cells showed increased IC50 and reduced apoptosis upon CHZ868 reflecting acquired resistance to JAK2 inhibition. Among &amp;gt;2,500 differential phospho-sites, MAPK pathway activation was most prominent, while JAK2-STAT3/5 remained suppressed. Altered histone occupancy promoting AP-1/GATA binding motif exposure associated with upregulated AXL kinase and enriched RAS target gene profiles. AXL knockdown resensitized MPN cells and combined JAK2/AXL inhibition using bemcentinib or gilteritinib reduced IC50 to levels of sensitive cells. While resistant cells induced tumor growth in NOD/SCID gamma mice despite JAK2 inhibition, JAK2/AXL inhibition largely prevented tumor progression. Because inhibitors of MAPK pathway kinases such as MEK are clinically used in other malignancies, we evaluated JAK2/MAPK inhibition with trametinib to interfere with AXL/MAPK-induced resistance. Tumor growth was halted similarly to JAK2/AXL inhibition and in a systemic cell line–derived mouse model, marrow infiltration was decreased supporting dependency on AXL/MAPK. Conclusions: We report on a novel mechanism of AXL/MAPK-driven escape from type II JAK2 inhibition, which is targetable at different nodes. This highlights AXL as mediator of acquired resistance warranting inhibition to enhance sustainability of JAK2 inhibition in MPN.
A Phase I/II Study of GSK525762 Combined with Fulvestrant in Patients with Hormone Receptor–positive/HER2-negative Advanced or Metastatic Breast Cancer
Authors: David W. Cescon, John Hilton, Serafin Morales Murilo, Rachel M. Layman, Timothy Pluard, Belinda Yeo, In Hae Park, Louise Provencher, Sung-Bae Kim, Young-Hyuck Im, Anastasia Wyce, Anu Shilpa Krishnatry, Kirsty Hicks, Qu Zhang, Olena Barbash, Ahmed Khaled, Thierry Horner, Arindam Dhar, Mafalda Oliveira, Joseph A. Sparano
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Endocrine-based therapy is the initial primary treatment option for hormone receptor–positive and human epidermal growth factor receptor 2-negative (HR+/HER2−) metastatic breast cancer (mBC). However, patients eventually experience disease progression due to resistance to endocrine therapy. Molibresib (GSK525762) is a small-molecule inhibitor of bromodomain and extraterminal (BET) family proteins (BRD2, BRD3, BRD4, and BRDT). Preclinical data suggested that the combination of molibresib with endocrine therapy might overcome endocrine resistance. This study aimed to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy [objective response rate (ORR)] of molibresib combined with fulvestrant in women with HR+/HER2− mBC. Patients and Methods: In this phase I/II dose-escalation and dose-expansion study, patients received oral molibresib 60 or 80 mg once daily in combination with intramuscular fulvestrant. Patients enrolled had relapsed/refractory, advanced/metastatic HR+/HER2− breast cancer with disease progression on prior treatment with an aromatase inhibitor, with or without a cyclin-dependent kinase 4/6 inhibitor. Results: The study included 123 patients. The most common treatment-related adverse events (AE) were nausea (52%), dysgeusia (49%), and fatigue (45%). At a 60-mg dosage of molibresib, &amp;gt;90% of patients experienced treatment-related AE. Grade 3 or 4 treatment-related AE were observed in 47% and 48% of patients treated with molibresib 60 mg and molibresib 80 mg, respectively. The ORR was 13% [95% confidence interval (CI), 8–20], not meeting the 25% threshold for proceeding to phase II. Among 82 patients with detected circulating tumor DNA and clinical outcome at study enrollment, a strong association was observed between the detection of copy-number amplification and poor progression-free survival (HR, 2.89; 95% CI, 1.73–4.83; P &amp;lt; 0.0001). Conclusions: Molibresib in combination with fulvestrant did not demonstrate clinically meaningful activity in this study.
SUMOylation-Driven mRNA Circularization Enhances Translation and Promotes Lymphatic Metastasis of Bladder Cancer
Authors: Yue Zhao, Jiancheng Chen, Hanhao Zheng, Yuming Luo, Mingjie An, Yan Lin, Mingrui Pang, Yuanlong Li, Yao Kong, Wang He, Tianxin Lin, Changhao Chen
Journal: Cancer Research (2023)

Abstract Aberrant gene expression is a prominent feature of metastatic cancer. Translational initiation is a vital step in fine-tuning gene expression. Thus, exploring translation initiation regulators may identify therapeutic targets for preventing and treating metastasis. Herein, we identified that DHCR24 was overexpressed in lymph node (LN) metastatic bladder cancer and correlated with poor prognosis of patients. DHCR24 promoted lymphangiogenesis and LN metastasis of bladder cancer in vitro and in vivo. Mechanistically, DHCR24 mediated and recognized the SUMO2 modification at lysine 108 of hnRNPA2B1 to foster TBK1 mRNA circularization and eIF4F initiation complex assembly by enhancing hnRNPA2B1–eIF4G1 interaction. Moreover, DHCR24 directly anchored to TBK1 mRNA 3′-untranslated region to increase its stability, thus forming a feed forward loop to elevate TBK1 expression. TBK1 activated PI3K/Akt signaling to promote VEGFC secretion, resulting in lymphangiogenesis and LN metastasis. DHCR24 silencing significantly impeded bladder cancer lymphangiogenesis and lymphatic metastasis in a patient-derived xenograft model. Collectively, these findings elucidate DHCR24-mediated translation machinery that promotes lymphatic metastasis of bladder cancer and supports the potential application of DHCR24-targeted therapy for LN-metastatic bladder cancer. Significance: DHCR24 is a SUMOylation regulator that controls translation initiation complex assembly and orchestrates TBK1 mRNA circularization to activate Akt/VEGFC signaling, which stimulates lymphangiogenesis and promotes lymph node metastasis in bladder cancer.
DNA Mutational Profiling in Patients With Colorectal Cancer Treated With Standard of Care Reveals Differences in Outcome and Racial Distribution of Mutations
Authors: Federico Innocenti, Wancen Mu, Xueping Qu, Fang-Shu Ou, Omar Kabbarah, Charles David Blanke, Alan P. Venook, Heinz-Josef Lenz, Naim U. Rashid
Journal: Journal of Clinical Oncology (2023)

CALGB (Alliance)/SWOG 80405 was a randomized phase III trial that in first-line patients with metastatic colorectal cancer (mCRC) treated with bevacizumab or cetuximab with chemotherapy. We aimed to discover novel mutated genes associated with prognosis and differential response to therapy with the biologics.
Isolated Adrenal Metastases of Castration-Resistant Prostate Cancer
Authors: Edanur Topal, Duygu Has Simsek, Sezai Vatansever, Yasemin Sanli, Serkan Kuyumcu
Journal: Clinical Nuclear Medicine (2023)

Abstract We present isolated bilateral adrenal metastases successfully treated with 177 Lu-PSMA in a 66-year-old man diagnosed with castration-resistant prostate cancer. The patient had progression under chemotherapy as depicted by 68 Ga-PSMA PET/CT showing intense bilateral PSMA uptake in the adrenal masses, and metastasis-directed therapies were considered as the first option for improving survival because the patient was oligometastatic. However, surgery and radiotherapy were not justifiable options due to the high risk of definitive adrenal insufficiency; therefore, the patient received 4 cycles of 177 Lu-PSMA treatment. 68 Ga-PSMA PET/CT showed near-complete response in bilateral adrenal metastases, and no sign of adrenal insufficiency was observed during follow-up.
Integration of Transcriptomic Features to Improve Prognosis Prediction of Pediatric Acute Myeloid Leukemia With KMT2A Rearrangement
Authors: Jun Li, Suyu Zong, Yang Wan, Min Ruan, Li Zhang, Wenyu Yang, Xiaojuan Chen, Yao Zou, Yumei Chen, Ye Guo, Peng Wu, Yingchi Zhang, Xiaofan Zhu
Journal: HemaSphere (2023)

Lysine methyltransferase 2A-rearranged acute myeloid leukemia (KMT2A-r AML) is a special entity in the 2022 World Health Organization classification of myeloid neoplasms, characterized by high relapse rate and adverse outcomes. Current risk stratification was established on the treatment response and translocation partner of KMT2A. To study the transcriptomic feature and refine the current stratification of pediatric KMT2A-r AML, we analyzed clinical and RNA sequencing data of 351 patients. By implementing least absolute shrinkage and selection operator algorithm, we identified 7 genes (KIAA1522, SKAP2, EGFL7, GAB2, HEBP1, FAM174B, and STARD8) of which the expression levels were strongly associated with outcomes. We then developed a transcriptome-based score, dividing patients into 2 groups with distinct gene expression patterns and prognosis, which was further validated in an independent cohort and outperformed the LSC17 score. We also found cell cycle, oxidative phosphorylation, and metabolism pathways were upregulated in patients with inferior outcomes. By integrating clinical characteristics, we proposed a simple-to-use prognostic scoring system with excellent discriminability, which allowed us to distinguish allogeneic hematopoietic stem cell transplantation candidates more precisely. In conclusion, pediatric KMT2A-r AML is heterogenous on transcriptomic level and the newly proposed scoring system combining clinical characteristics and transcriptomic features can be instructive in clinical routines.
Amelioration of Tau and ApoE4-linked glial lipid accumulation and neurodegeneration with an LXR agonist
Authors: Alexandra Litvinchuk, Jung H. Suh, Jing L. Guo, Karin Lin, Sonnet S. Davis, Nga Bien-Ly, Eric Tycksen, G. Travis Tabor, Javier Remolina Serrano, Melissa Manis, Xin Bao, Choonghee Lee, Megan Bosch, Enmanuel J. Perez, Carla M. Yuede, Anil G. Cashikar, Jason D. Ulrich, Gilbert Di Paolo, David M. Holtzman
Journal: Neuron (2023)
Tumor macrophage functional heterogeneity can inform the development of novel cancer therapies
Authors: Ibraheem Nasir, Conor McGuinness, Ashleigh R. Poh, Matthias Ernst, Phillip K. Darcy, Kara L. Britt
Journal: Trends in Immunology (2023)

Macrophages represent a key component of the tumor microenvironment (TME) and are largely associated with poor prognosis. Therapeutic targeting of macrophages has historically focused on inhibiting their recruitment or reprogramming their phenotype from a protumor (M2-like) to an antitumor (M1-like) one. Unfortunately, this approach has not provided clinical breakthroughs that have changed practice. Emerging studies utilizing single-cell RNA-sequencing (scRNA-seq) and spatial transcriptomics have improved our understanding of the ontogeny, phenotype, and functional plasticity of macrophages. Overlaying the wealth of current information regarding macrophage molecular subtypes and functions has also identified novel therapeutic vulnerabilities that might drive better control of tumor-associated macrophages (TAMs). Here, we discuss the functional profiling of macrophages and provide an update of novel macrophage-targeted therapies in development.
Mandatory pay gap reporting is key to achieving workforce gender equality in the global health sector
Authors: Victoria Olarewaju, Jasmine Gideon, Aaron Koay
Journal: BMJ (2023)

Tackling the gender pay gap is essential for a more inclusive global health sector, but progress towards closing the gap has remained slow, highlighting the need for better transparency and accountability. Mandatory reporting is an important first step in pushing for change, say <b>Victoria Olarewaju and colleagues</b>
Platelets mediate the clearance of senescent red blood cells by forming prophagocytic platelet-cell complexes
Authors: Dian C. Ningtyas, Florentina Leitner, Huma Sohail, Yee Lin Thong, Sarah M. Hicks, Sidra Ali, Megan Drew, Kiran Javed, Jiwon Lee, Enny Kenangalem, Jeanne R. Poespoprodjo, Nicholas M. Anstey, Melanie Rug, Philip Y.-I. Choi, Steven Kho, Elizabeth E. Gardiner, Brendan J. McMorran
Journal: Blood (2023)

In humans, ∼0.1% to 0.3% of circulating red blood cells (RBCs) are present as platelet-RBC (P-RBC) complexes, and it is 1% to 2% in mice. Excessive P-RBC complexes are found in diseases that compromise RBC health (eg, sickle cell disease and malaria) and contribute to pathogenesis. However, the physiological role of P-RBC complexes in healthy blood is unknown. As a result of damage accumulated over their lifetime, RBCs nearing senescence exhibit physiological and molecular changes akin to those in platelet-binding RBCs in sickle cell disease and malaria. Therefore, we hypothesized that RBCs nearing senescence are targets for platelet binding and P-RBC formation. Confirming this hypothesis, pulse-chase labeling studies in mice revealed an approximately tenfold increase in P-RBC complexes in the most chronologically aged RBC population compared with younger cells. When reintroduced into mice, these complexes were selectively cleared from the bloodstream (in preference to platelet-free RBC) through the reticuloendothelial system and erythrophagocytes in the spleen. As a corollary, patients without a spleen had higher levels of complexes in their bloodstream. When the platelet supply was artificially reduced in mice, fewer RBC complexes were formed, fewer erythrophagocytes were generated, and more senescent RBCs remained in circulation. Similar imbalances in complex levels and senescent RBC burden were observed in humans with immune thrombocytopenia (ITP). These findings indicate that platelets are important for binding and clearing senescent RBCs, and disruptions in platelet count or complex formation and clearance may negatively affect RBC homeostasis and may contribute to the known risk of thrombosis in ITP and after splenectomy.
A mechanism for hereditary angioedema caused by a methionine-379–to–lysine substitution in kininogens
Authors: S. Kent Dickeson, Sunil Kumar, Mao-fu Sun, Maxim Litvak, Tracey Z. He, Dennis R. Phillips, Elijah T. Roberts, Edward P. Feener, Ruby H. P. Law, David Gailani
Journal: Blood (2023)
ABL1 kinase plays an important role in spontaneous and chemotherapy-induced genomic instability in multiple myeloma
Authors: Subodh Kumar, Srikanth Talluri, Jiangning Zhao, Chengcheng Liao, Lakshmi B. Potluri, Leutz Buon, Shidai Mu, Jialan Shi, Chandraditya Chakraborty, Yu-Tzu Tai, Mehmet K. Samur, Nikhil C. Munshi, Masood A. Shammas
Journal: Blood (2023)

Genomic instability contributes to cancer progression and is at least partly due to dysregulated homologous recombination (HR). Here, we show that an elevated level of ABL1 kinase overactivates the HR pathway and causes genomic instability in multiple myeloma (MM) cells. Inhibiting ABL1 with either short hairpin RNA or a pharmacological inhibitor (nilotinib) inhibits HR activity, reduces genomic instability, and slows MM cell growth. Moreover, inhibiting ABL1 reduces the HR activity and genomic instability caused by melphalan, a chemotherapeutic agent used in MM treatment, and increases melphalan's efficacy and cytotoxicity in vivo in a subcutaneous tumor model. In these tumors, nilotinib inhibits endogenous as well as melphalan-induced HR activity. These data demonstrate that inhibiting ABL1 using the clinically approved drug nilotinib reduces MM cell growth, reduces genomic instability in live cell fraction, increases the cytotoxicity of melphalan (and similar chemotherapeutic agents), and can potentially prevent or delay progression in patients with MM.
Absolute and relative risk of violent victimisation and perpetration following onset of mental illness: a Danish register-based study
Authors: Kimberlie Dean, Thomas Munk Laursen, Carey Marr, Carsten B. Pedersen, Roger T. Webb, Esben Agerbo
Journal: The Lancet Regional Health - Europe (2023)

Previous research has suggested that people with severe mental illness are at elevated risk of both violence perpetration and violent victimisation, with risk of the latter being perhaps greater than the former. However, few studies have examined risk across both outcomes.
Radio-Guided Occult Lesion Localization With 99mTc for the Localization of Nonpalpable Melanoma and Soft Tissue Sarcoma Lesions: A Feasibility Study
Authors: Sophie J.M. Reijers, Fleur J. Mook, Harald C. Groen, Yvonne Schrage, Marcel P.M. Stokkel, Maarten L. Donswijk, Winan J. van Houdt
Journal: Clinical Nuclear Medicine (2023)

Purpose of the Report Localization techniques are needed to facilitate resection of nonpalpable lesions. In this study, the feasibility of radio-guided occult lesion localization (ROLL) with 99m Tc is investigated for the localization of nonpalpable, small, suspicious, or proven melanoma or soft tissue sarcoma lesions at various locations throughout the body. Patients and Methods Patients with nonpalpable, suspicious, or proven melanoma or soft tissue sarcoma lesions were selected for this study. Within 24 hours before surgery, a median dose of 33.92 MBq 99m Tc-labeled human albumin particles ( 99m Tc-NA or 99m Tc-MAA) was injected in the lesion under ultrasound guidance. A hand-held gamma probe was used to detect the radioactive signal and guidance during surgery. Results In this study, 20 patients with a total of 25 lesions were included and analyzed. The median size of the lesions was 1.8 cm (interquartile range [IQR], 1.8–4.0 cm), of which 44% were intramuscular located and 36% were subcutaneous, and 20% consisted of suspicious lymph nodes, mostly in the lower extremity. At median 4 hours (IQR, 3–6 hours) postinjection, 99m Tc ROLL showed a 100% intraoperative identification rate with proper signal identification with the gamma probe in all patients. With a median surgery time of 76 minutes (IQR, 45–157 minutes), all targeted lesions could be resected without 99m Tc-related complications, resulting in 88% microscopically margin-negative resection. No reoperations were needed for the same lesion. Conclusions The 99m Tc ROLL procedure is feasible for the localization and excision of small, nonpalpable melanoma and soft tissue sarcoma lesions at various locations in the body.
Evidence Synthesis of Observational Studies in Environmental Health: Lessons Learned from a Systematic Review on Traffic-Related Air Pollution
Authors: Hanna Boogaard, Richard W. Atkinson, Jeffrey R. Brook, Howard H. Chang, Gerard Hoek, Barbara Hoffmann, Sharon K. Sagiv, Evangelia Samoli, Audrey Smargiassi, Adam A. Szpiro, Danielle Vienneau, Jennifer Weuve, Frederick W. Lurmann, Francesco Forastiere
Journal: Environmental Health Perspectives (2023)

There is a long tradition in environmental health of using frameworks for evidence synthesis, such as those of the U.S. Environmental Protection Agency for its Integrated Science Assessments and the International Agency for Research on Cancer Monographs. The framework, Grading of Recommendations Assessment, Development, and Evaluation (GRADE), was developed for evidence synthesis in clinical medicine. The U.S. Office of Health Assessment and Translation (OHAT) elaborated an approach for evidence synthesis in environmental health building on GRADE.
Survival in primary hemophagocytic lymphohistiocytosis, 2016 to 2021: etoposide is better than its reputation
Authors: Svea Böhm, Katharina Wustrau, Jana Pachlopnik Schmid, Seraina Prader, Martina Ahlmann, Joanne Yacobovich, Rita Beier, Carsten Speckmann, Wolfgang Behnisch, Marianne Ifversen, Michael Jordan, Rebecca Marsh, Nora Naumann-Bartsch, Christine Mauz-Körholz, Manfred Hönig, Ansgar Schulz, Iwona Malinowska, Melissa Hines, Kim E. Nichols, Juana Gil-Herrera, Julie-An Talano, Bruce Crooks, Renata Formankova, Norbert Jorch, Shahrzad Bakhtiar, Ingrid Kühnle, Monika Streiter, Michaela Nathrath, Alexandra Russo, Matthias Dürken, Peter Lang, Caroline Lindemans, Jan-Inge Henter, Kai Lehmberg, Stephan Ehl
Journal: Blood (2023)